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The role of the matrix metalloproteinases in human endometrial and ovarian cycles.

The matrix metalloproteinases (MMPs) are part of an expanded family of proteins called the astacin family of zinc metalloproteinases. The MMPs, probably balanced by their tissue inhibitors of metalloproteinases (TIMPs), are essential effectors of developmental processes participating in cell migration, cell proliferation, apoptosis and tissue morphogenesis. The MMPs regulate the function of biologically active molecules as well as fulfilling an important role in endothelial cell invasion, angiogenesis and in tumor progression. The dynamic normal physiology of the human reproductive system involves almost all of the above-mentioned aspects of MMPs activity. This review presents and discusses new insights into the role of MMPs, and their TIMPs, in human endometrial cycle and ovarian function.

Endometrium↗

Maturation and developmental stage-related changes in fetal globin gene expression are reproduced in transiently transfected primary adult human erythroblasts.

A novel system is described, which uses transfection of primary human erythroblasts for the study of gene regulation in differentiating human red cells. This system includes a protocol for liquid culture of erythroid progenitors, which reproduces developmental differences in globin gene expression found between adult and cord blood as well as the maturation-related changes in fetal globin levels observed in adult cells. Reporter constructs driven by globin gene promoters were electroporated into adult and cord blood-derived erythroblasts at different time points during culture. Both the developmental stage and maturation-related differences in endogenous fetal and adult globin gene expression could be reproduced by the transiently transfected reporter constructs. Transfection of primary human erythroblasts during differentiation provides a previously unavailable opportunity to study dynamic aspects of erythropoiesis.

Adult↗

Chemotactic cell movement during development.

Chemotaxis is an important mechanism controlling cell migration over either short or long distances during different developmental processes. Small rapid diffusing chemo-attractants are detected through serpentine, G protein coupled receptors through graded activation of receptors along the length of the cell. Internal amplification results in polarisation of the actin and myosin cytoskeletal dynamics along the gradient and directed movement. The dynamics of these processes can now be studied in individual cells in developing organisms. Slow diffusing chemo-attractants such as growth factors, providing short-range guidance information, often signal through tyrosine kinase receptors. Detection of these signals may involve the active extension of very long cellular process up growth factor gradients, followed by translocation of the cell in the direction of the gradient.

Animals↗

Substrates and routes of migration of early generated neurons in the developing rat thalamus.

We investigated the substrates supporting neuronal migration, and its routes, during early thalamic development in the rat. Neurons and axonal and glial fibres were identified in embryos with single and double immunohistochemistry; dynamic data were obtained with cell tracers in short-term organotypic cultured slices. The earliest thalamic neurons, originating from the ventricular neuroepithelium between embryonic days 13 and 15, include those of the reticular thalamic nucleus. At this developmental stage, calretinin, calbindin or gamma-aminobutyric acid immunostaining revealed both radially and nonradially orientated neurons in the region of reticular thalamic migration, between the dorsal and ventral thalamic primordia. In cultured slices, injections of fluorescent dyes in the neuroepithelium labelled neurons in a migratory stream along radial glia in the same zone. Some labelled fusiform cells departed from this radial trajectory along orthogonal routes within the dorsal thalamus. Confocal microscopy revealed nonradially orientated neurons in close apposition with a fibre system parallel to the lateral thalamic surface. These fibres expressed axonal markers, including the intermediate filament protein alpha-internexin and a polysialylated form of neuronal cell adhesion molecule. Active migration of nonradially orientated neurons along neuronal substrates was confirmed in living cultured slices. In addition, in vitro and ex vivo experiments revealed neurons migrating tangentially in association with glial fibres. These results provide novel evidence that: (i) early generated thalamic neurons follow nonradial routes in addition to glia-linked radial migration; and (ii), nonradially migrating thalamic neurons move along both glial and axonal substrates, which could represent a distinctive feature of thalamic development.

Animals↗

Unique issues in pediatric spinal cord injury.

Spinal cord injuries are devastating events, and they are particularly tragic when they affect children or adolescents who have barely had an opportunity to experience life. Of the approximately 10,000 individuals who sustain spinal cord injury each year in the United States, 3% to 5% occur in individuals younger than 15 years of age and approximately 20% occur in those younger than 20 years of age (Nobunaga, Go, & Karunas, 1999). Because of the growth and development inherent in children and adolescents and the unique manifestations and complications associated with spinal cord injuries, management must be developmentally based and directed to the individual's special needs (Vogel, 1997). The many unique facets of pediatric spinal cord injuries are addressed in this article. They clearly delineate the need for care that is responsive to the dynamic changes that occur with growth and development. The multidisciplinary team, combined with a focus on family-centered care, is essential in pediatric spinal cord injuries.

Adolescent↗

A biologically-based dose-response model for developmental toxicology.

The methods currently used to evaluate the risk of developmental defects in humans from exposure to potential toxic agents do not reflect biological processes in extrapolating estimated risks to low doses and from test species to humans. We develop a mathematical model to describe aspects of the dynamic process of organogenesis, based on branching process models of cell kinetics. The biological information that can be incorporated into the model includes timing and rates of dynamic cell processes such as differentiation, migration, growth, and replication. The dose-response models produced can explain patterns of malformation rates as a function of both dose and time of exposure, resulting in improvements in risk assessment and understanding of the underlying mechanistic processes. To illustrate the use of the model, we apply it to the prediction of the effects of methylmercury on brain development in rats.

Abnormalities, Drug-Induced↗

Structural magnetic resonance imaging of the adolescent brain.

Magnetic resonance imaging (MRI) provides accurate anatomical brain images without the use of ionizing radiation, allowing longitudinal studies of brain morphometry during adolescent development. Results from an ongoing brain imaging project being conducted at the Child Psychiatry Branch of the National Institute of Mental Health indicate dynamic changes in brain anatomy throughout adolescence. White matter increases in a roughly linear pattern, with minor differences in slope in the four major lobes (frontal, parietal, temporal, occipital). Cortical gray matter follows an inverted U-shape developmental course with greater regional variation than white matter. For instance, frontal gray matter volume peaks at about age 11.0 years in girls and 12.1 years in boys, whereas temporal gray matter volume peaks at about age at 16.7 years in girls and 16.2 years in boys. The dorsal lateral prefrontal cortex, important for controlling impulses, is among the latest brain regions to mature without reaching adult dimensions until the early 20s. The details of the relationships between anatomical changes and behavioral changes, and the forces that influence brain development, have not been well established and remain a prominent goal of ongoing investigations.

Adolescent↗

The spatial and temporal deployment of Dfd and Scr transcripts throughout development of Drosophila.

In Drosophila, the Deformed (Dfd) and Sex combs reduced (Scr) genes determined the developmental pathways followed by the most anterior metameric units. Using in situ hybridization, we have monitored the spatial distributions of transcripts from these two genes. Dfd RNA accumulates in parasegments 0 and 1; Scr RNA accumulation shows a dynamic pattern spanning parasegments 2 and 3. The expression of Dfd and Scr seems to change from parasegmental to segmental during formation of the gnathal appendages. Both genes are transcribed during imaginal development: Dfd in a portion of the eye-antennal disc; Scr in the labial and prothoracic discs. In addition, we find Scr RNA in the adepithelial cells of all mesothoracic discs.

Animals↗

Evolutional neurologic evaluation of seven year-old children born prematurely.

A sample of 51 children aged 7 with a history of prematurity was compared to 44 age-matched children who were born at term at the HCPA. The premature children had had gestational ages up to 37 weeks and 6 days and were born weighing less than 2,500 g. The control group consisted of children born with gestational age between 38 and 42 weeks and weights above 2,500 g. The evaluation criteria were clinical examination, neurological examination and the evolutional neurological evaluation (ENE). The results pointed out that impulsiveness, aggressiveness, disorganization and enuresis were prevalent symptoms of developmental disturbances in the sample of prematures. Alterations at neurological examination did not discriminate between the two groups, although cerebral palsy occurred only in the group of prematures. The ENE functions which differentiated the two groups studied were dynamic balance, appendicular and trunk-limb coordination and motor persistence.

Birth Weight↗

Developmental basis of limb evolution.

Can developmental processes account for vertebrate limb homology, the overall similarity of definitive limb structure despite differences in different taxa which often relate to evolutionary adaptations? Relevant evidence is from molecular studies, from 'cut & paste' experimental embryology and from classical descriptive accounts of embryology and structure. There is striking evidence of a similar pattern of homologous regulatory gene expression (eg Shh, and Hox A & D genes) in tetrapod limb buds, and both similarity and differences when these are compared with expression patterns in a teleost fish paired fin bud. But these findings are as yet from too few tetrapod species (chick and mouse) to permit a 'molecular bauplan' for the limb to be proposed with any certainty. Further, the identification of similar networks of regulatory genes common to non-homologous developmental systems limits possibilities for finding a basis for classical structural homology in terms of expression of system-specific genes or gene networks. An integrated approach is needed, combining evidence from the fin-limb transition, and from study of the patterns and processes of amphibian and avian limb embryology, and this points towards a conserved developmental bauplan for the pentadactyl skeleton of the type earlier proposed by Alberch. Key features include the digital arch, restriction of digit number to a maximum of 5 and stereotyped connections between prechondrogenic condensations. But this is a dynamic and not rigidly fixed bauplan. It has no single set of skeletal elements (except proximally), since the position of joint formation in the prechondrogenic condensations is not stereotyped. Urodele amphibians in particular demonstrate heterochronic differences in the timing of events. Heterochrony may underlie some of the important changes in the pentadactyl pattern during evolution.

Animals↗

Developmental validation of a real-time quantitative PCR assay for automated quantification of human DNA.

Our laboratory has developed an automated real-time quantitative PCR assay for detecting human DNA. The assay utilizes an in-house, custom-designed TaqMan-MGB sequence-specific probe (CFS-HumRT) and the ABD 7900HT SDS platform. Developmental validation has followed TWGDAM (1) guidelines and demonstrates that the assay is primate specific, is highly sensitive, yields consistent results, and works with human DNA extracted from a variety of body fluid stains. When operating within the dynamic range of the system using high-quality DNA samples. the technique yields similar quantification results to our current QuantiBlot assay with the added benefit of time saving through automation. Furthermore, the QPCR assay identifies how much amplifiable DNA is in a sample and thus has the potential to predict PCR success in downstream applications such as STR analysis.

Animals↗

Day hospital treatment for borderline adolescents.

Short-term psychiatric hospitalization for acute disturbances in adolescents has little effect on underlying developmental deficits. A day hospital treatment program based on psychoanalytic object relations concepts can provide an alternative to costly long-term inpatient hospital adolescent programs while limiting regressive and destructive behavior. An understanding of the characteristics and dynamics of borderline adolescent patients provided the basis for practical approaches that also were helpful to other patients. A review of the literature on the day treatment of borderline patients precedes a discussion of the diagnosis and dynamics of borderline adolescents. This is followed by a description of the methods utilized in a day hospital program whose goal was to potentiate a successful start of a longer-term psychotherapeutic process that could continue after discharge. Difficulties in prognosis and in designing verifying research are discussed.

Adolescent↗

Factors to consider when selecting animal models for postnatal teratology studies.

This presentation identifies some of the factors which should be considered when choosing a particular animal as a model to predict postnatal teratogenic hazards to man. The developmental pharmacologist-toxicologist must consider in concert the potential interactions of a xenobiotic on the mother, her placenta, her fetus, and her nursing young. Since the physiology of each of these components is in a state of dynamic flux during gestation and/or postnatal development, the critical time at which to expose the mother or her progeny to a chemical will vary widely from species to species and organ to organ. The identification of critical periods during the perinatal period may be quite difficult because the physiological or behavioral changes in the adult organism which signal that perinatal teratogenic effects have occurred are frequently subtle. Much research is still needed on the comparative aspects of maternal, placental, fetal, and neonatal pharmacokinetics and pharmacodynamics. We are not ready to intelligently evaluate large numbers of chemicals as potential postnatal teratogens for man.

Adaptation, Biological↗

Dynamics of synapsin I gene expression during the establishment and restoration of functional synapses in the rat hippocampus.

Synapse development and injury-induced reorganization have been extensively characterized morphologically, yet relatively little is known about the underlying molecular and biochemical events. To examine molecular mechanisms of synaptic development and rearrangement, we looked at the developmental pattern of expression of the neuron-specific gene synapsin I in granule cell neurons of the dentate gyrus and their accompanying mossy fibers during the main period of synaptogenic differentiation in the rat hippocampus. We found a significant difference between the temporal expression of synapsin I messenger RNA in dentate granule somata and the appearance of protein in their mossy fiber terminals during the postnatal development of these neurons. Next, to investigate the regulation of neuron-specific gene expression during the restoration of synaptic contacts in the central nervous system, we examined the expression of the synapsin I gene following lesions of hippocampal circuitry. These studies show marked changes in the pattern and intensity of synapsin I immunoreactivity in the dendritic fields of dentate granule cell neurons following perforant pathway transection. In contrast, changes in synapsin I messenger RNA expression in target neurons, and in those neurons responsible for the reinnervation of this region of the hippocampus, were not found to accompany new synapse formation. On a molecular level, both developmental and lesion data suggest that the expression of the synapsin I gene is tightly regulated in the central nervous system, and that considerable changes in synapsin I protein may occur in neurons without concomitant changes in the levels of its messenger RNA. Finally, our results suggest that the appearance of detectable levels of synapsin I protein in in developing and sprouting synapses coincides with the acquisition of function by those central synapses.

Acetylcholinesterase↗

Developmental changes in lysosome morphology and function Leishmania parasites.

The endocytic pathway of Leishmania parasites has recently come under intense research focus through the development of several markers for various compartments of this pathway. Through these studies a novel multivesicular tubule lysosome has been discovered in promastigote-stage parasites. This organelle has a highly dynamic role during parasite growth and differentiation. This review discusses recent insights into the Leishmania lysosome with respect to its organisation within the endocytic pathway, stage-specific functions, and biogenesis.

Animals↗

[Psychopathology of development and structural dynamics].

The mental structure provides every human with a potential repertoire of behavior. In every interaction a reactivation of past actualization- and representation processes concerning the particular prevailing context takes place. A child's mental structure should not be devaluated in comparison to a structure of an adult person. Levels of functioning depend on the developmental age. Structural dispositions consist of represented experiences of interaction. The so-called affect attenuement plays an important part in individual affect regulation. If the structural representation follows mechanisms of memory, procedural structural dispositions may be postulated, which affect the behavior besides iconic and symbolic representations. Within the structure affect dispositions are integrated. They are able to give value to certain contents of experience and reexperience. Disorders in the development of empathy are connected with impairments of the structural development. By inherent faintness of the regulation of affects or by sensitization and traumatization processes, which involve dissociative phenomena, the affective load of representations can be changed. This may result in structural deficits.

Affect↗

Mitogen-activated protein kinase dynamics during the meiotic G2/MI transition of mouse spermatocytes.

Cellular and genetic approaches were used to investigate the requirements for activation during spermatogenesis of the extracellular signal-regulated protein kinases (ERKs), more commonly known as the mitogen-activated protein kinases (MAPKs). The MAPKS and their activating kinases, the MEKs, are expressed in specific developmental patterns. The MAPKs and MEK2 are expressed in all premeiotic germ cells and spermatocytes, while MEK1 is not expressed abundantly in pachytene spermatocytes. Phosphorylated (active) variants of these kinases are diminished in pachytene spermatocytes. Treatment of pachytene spermatocytes with okadaic acid (OA), to induce transition from meiotic prophase to metaphase I (G2/MI), resulted in phosphorylation and enzymatic activation of ERK1/2. However, U0126, an inhibitor of the ERK-activating kinases, MEK1/2, did not inhibit OA-induced MAPK activation or chromosome condensation. Analysis of spermatocytes lacking MOS, a mitogen-activated protein kinase kinase kinase responsible for MEK and MAPK activation, revealed that MOS is not required for OA-induced activation of the MAPKs. OA-induced MAPK activation was inhibited by butyrolactone I, an inhibitor of cyclin-dependent kinases 1 and 2 (CDK1, CDK2); thus, these kinases may regulate MAPK activity. Additionally, spermatocytes lacking CDC25C condensed bivalent chromosomes and activated both MPF and MAPKs in response to OA treatment; therefore, there is a CDC25C-independent pathway for MPF and MAPK activation. These studies reveal that spermatocytes do not require either MOS or CDC25C for onset of the meiotic division phase or for activation of MPF and the MAPKs, thus implicating a novel pathway for activation of the ERK1/2 MAPKs in spermatocytes.

4-Butyrolactone↗

Developmental expression of the four plasma membrane calcium ATPase (Pmca) genes in the mouse.

The plasma membrane calcium ATPases are critical components in the regulation of cellular calcium homeostasis and signaling. In mammals, there are 4 Pmca genes, and information on the cellular and tissue distribution of their expression during development will provide insight into the regulation and possible function of each Pmca isoform. Using specific probes and in situ hybridization, we found that the four Pmca genes are expressed in spatially overlapping but distinct patterns in the mouse embryo. The dynamic temporal patterns of expression indicate that the individual isoforms are subject to both positive and negative regulation. The differential and restricted expression of Pmca genes supports the notion that they play unique functional roles in mammalian development.

Animals↗